EP0287340A2

EP0287340A2 - Novel acylation process for the synthesis of HMG-COA reductase inhibitors

Info

Publication number: EP0287340A2
Application number: EP88303304A
Authority: EP
Inventors: Ann Elisabeth Decamp; Leonard M. Weinstock; Thomas R. Verhoeven
Original assignee: Merck and Co Inc
Current assignee: Merck and Co Inc
Priority date: 1987-04-15
Filing date: 1988-04-13
Publication date: 1988-10-19
Anticipated expiration: 2008-04-13
Also published as: US4845237A; EP0287340A3; CA1317295C; DE3884445D1; EP0287340B1; IE62185B1; JPS63277668A; JP2688357B2; DE3884445T2; IE881128L

Abstract

A novel acylation process using an alkali metal bromide and a dialkylaminopyridine to form a sterically hindered ester functionality from an alkanoyl chloride and an alcohol is disclosed.

Description

BACKGROUND OF THE INVENTION

Semi-synthetic and totally synthetic analogs of the natural fermentation products compactin and mevinolin have been found to be useful in limiting cholesterol biosynthesis by inhibiting the enzyme HMG-CoA reductase. Most semi-and totally synthetic analogs have the following general structural formulae:
or the dihydroxy acid, salt or ester thereof, wherein Z is
wherein
Z_zis H or OH; Z, is straight chain or branched C_1-10 alkyl, or C_{1 10} alkyl substituted with hydroxyl, phenyl or substituted phenyl, cycloalkyl. C, ₈ alkanoyloxy, alkylthio or phenylthio; a, b, c, and d represent optional double bonds, especially where b and d represent double bonds or a, b, c, and d are all single bonds; provided that when a is a double bond Q is
or Z is
and dihydroxy acid salts and esters thereof, where Z¹, Z², Z³, Z⁴ and Z⁵ independently are hydrogen, halogen, C, ₄alkyl, C_{1 4} haloalkyl, hydroxy-C, ₄alkyl C, salkanoyloxy C, ₄alkyl, or C₇ or C₁₁ aroyloxy-C, ₄alkyl wherein one of Z¹, Z², Z³, Z⁴, Z^S contains an ester functionality.
In the polyhydronapthyl derivatives the C-8-ester functionality is typically inserted by acylation of the C-8-alcohol with the appropriate acyl chloride. This reaction generally requires prolonged high temperatures (100°C, 18-36 hours) and large excesses of the often difficult to obtain acid chloride; however, even under these conditions the yields are low. In addition, the conditions of the acyl chloride reaction lead to a high percentage of undesired side product whereby a tertbutyldimethylsilyloxy radical, often present as a protecting group of alcohols, is eliminated from the δ-valerolactone moiety. Large amounts of starting alcohol and unconsumed acid chloride typically remain at the end of the reaction. These contaminants complicate isolation of product and result in lower yields of ester. The impurities also interfere with crystallization of subsequent intermediates. Similar problems may occur with acylation of alcohols in the biphenyl,lactone derivatives, particularly where the alcohol involved is sterically hindered.
Acyl bromides are known in the literature (Chem Abstracts, 72, 42844 (1970) and S.D. Saraf, M. Zakai, Synthesis, 612 (1973)). The synthesis of acyl iodides from acyl chlorides and sodium iodide in acetonitrile has been described by Hoffmann and Haase, Synthesis, 715, (1981).

DETAILED DESCRIPTION OF THE INVENTION

This invention relates to a novel acylation process for the preparation of antihypercholesterolemic compounds of structural formula (I),
wherein:

n is 0 to 5 5
R₁ and R₂ are independently H or C₁ 10 alkyl or R₁ and R₂ together with the carbon atom to which they are attached form a carbocyclic ring of 3 to 8 carbon atoms;
R₃ and R₄ are independently H or C₁₃ alkyl, C_{3 7}cycloalkyl, C_{1 3}alkylthio, phenyl, phenylthio or substituted phenyl in which the substituents are X and Y and when n is 2 to 5, each of the R₃s and R_4S are independently hydrogen, C, ₃ alkyl, C_{3 7}cycloalkyl or only one of the R₃S and R₄S is phenyl or substituted phenyl:
Rs is hydrogen, halogen, C_{1 10}alkyl, phenyl or substituted phenyl in which the substitutents are X and Y, or Rs is a group selected from:
- a) trialkylsilyloxy-C_{1 10}alkyl such as tert-butyldimethylsilyloxy-C_{1 10}alkyl or alkyldiarylsilyloxy-C₁- ₁₀alkyl such as tert-butyldiphenylsilyloxy-C_{1 10}alkyl or a like hydroxyl protecting group;
- b) triphenylmethylthio-C, ₁₀alkyl;
- c) C, ₈alkanoyloxy-C_{1 4}alkyl;
- d)
  in which m is 0 to 3 and R₇ is C₁ alkyl;
- e) R₈R₉
  in which R₈ and Rg are independently C_{1 5} alkyl or R₈ and R₉ together with the nitrogen atom to which they are attached form a heterocycle selected from piperidinyl, morpholinyl, pyrrolidinyl, piperazinyl or thiomorpholinyl;
- f) R₁₀
  CH₂)_m in which q is 0 to 2 and R₁₀ is C₁ alkyl or phenyl; X and Y independently are hydrogen, halogen, trifluromethyl, C_{1 3}alkyl, C_{1 3}alkyloxy, C_{1 3} alkylthio, di(C_{1 3}alkyl)N-
  and
  and OR is
  wherein
  - R₁₁ is hydrogen, or trialkylsilyloxy or alkyldiarylsilyloxy:
  - R_{1 3}is hydrogen or trialkylsilyloxy or alkyldiarylsilyloxy, a,b,c,d represent single bonds, one of a, b, c, or d represents a double bond or both a and c or both b and d represent double bonds, provided that when a is a double bond, A is
    or
    wherein
    - E is CH₂-CH₂ or CH = CH;
    - R_{1 5}R_{1 6} R₁ R₁₈ and R₁₉ independently are
    - hydrogen,
    - halogen,
    - C, 4 alkyl,
    - C_{1 4}haloalkyl,
    - oxy-C_{1 4} alkyl,
    - C_{1 8} alkanoyloxy-C₁₄ alkyl,
    - Cs ₁₂ aralkanoyloxy-C_{1 4} alkyl,
    - or C₇ or C₁₁ aroyloxy-C_{1 4} alkyl, with the proviso that one of R_{1 5} R₁ s R₁₇ R₁ and R₁₉ is oxy-C_{1 4}alkyl or oxy-wherein oxy-the oxygen is directly bonded to an aromatic ring of the biphenyl moiety;
    - which comprises combining,
    - an alkali metal bromide, dialkylaminopyridine and a compound of structure (i),
    - or a compound of structure (ii),
      wherein
    - R'₁ s R'_{1 6} R'₁₇ R'₁ are defined as R_{1 5} R_{1 6} R₁₇ R₁a R₁ respectively provided that when R₁ s R₁₆ s R₁₇ R₁ a or R₁ is oxy-C, ₄alkyl or oxy-then R'_{1 5} R'₁ s R'₁₇ R'_{1 8} or R'₁ is hydroxy-C_{1 4} alkyl or hydroxy-respectively;
    - in a solvent, to yield compound (I).

The invention is an improved method for the acylation of a hindered alcohol and/or a hindered acyl chloride. The fundamental principle is the activation of an acyl chloride using an alkali metal bromide/diaikylaminopyridine in reaction with an alcohol. Although the structure of the in situ generated acylating agent (2) is unknown it may be the acyl bromide (2a) or where the solvent is pyridine a pyridinium complex (2b) or a dialkylaminopyridinium complex (2c).
The sequence below displays a typical reaction scheme:

Unsaturated lactone byproduct
Following the sequence from (1) to (5) the acid chloride (1) reacts with an alkali metal bromide in a solvent followed by addition of dialkylaminopyridine. In this way the highly reactive acylating agent is available to acylate the alcohol (3) to give the ester (4) with virtually complete consumption of starting alcohol at a lower temperature (70°C) for shorter periods of time (6-8 hours). The reaction conditions of the instant invention are compatible with the silyl-protecting groups and thus only a minimal amount (1-2%) of unsaturated by-product (6) is formed. The increased purity of the product mixture greatly simplifies the isolation procedures.
As indicated above acylation following the instant invention is advantageous compared to using the acyl chloride itself, furthermore the instant invention is also advantageous compared to using acyl bromides. The instant invention uses acid chlorides which are readily prepared and purified and can be stored indefinitely due to their relative stability towards hydrolytic decomposition. In contrast, the preparation of acid bromides requires expensive, hard to obtain reagents and distillative purification of acyl bromides is hampered by their high boiling point and instability.
The invention disclosed is applicable to all acylation reactions between an acyl chloride and an alcohol which would occur albeit in low yield without the improvement conditions of the present invention. The invention is particularly applicable to hindered alcohol and acyl chloride reactants and such reactants which demonstrate elimination under normal acylation conditions.
One embodiment of this invention is the compounds prepared by the process disclosed herein where OR is the alkoxy residue of alcohol type (i):
I wherein OR is alkoxy residue of (i)
In one class of this embodiment the compounds prepared by the process of this invention are those compounds of formula (I) wherein R₅ is trialkylsilyoxy-C_{1 3}alkyl. In a subclass are the compounds prepared wherein R₁ is methyl, R₁ is hydrogen and a, b, c, d are all single bonds or one of b, c or d is a double bond or b and d are double bonds. illustrative of this subclass are the following compounds:

a) 6(R)-[2-[8(S)-(2,2-Dimethyl-4-tert-butyldimethylsilyloxy-butyryloxy)-2(S),6(R)-dimethyl-1,2,6,7,8,8a-(R)-hexahydronaphthyl-1 (S)ethyl]-4(R)-tert-butyldimethylsilyloxy-3,4,5,6-tetrahydro2H-pyran-2-one.
b) 6(R)2-[8(S)-(2,2-Dimethyl-4-tert-butyldimethylsilyloxy-pentanoyloxy)-2(S),6(R)-dimethyi-1,2,6,7,8,8a (R)-hexahydronaphthyl-1(S)ethyl]-4(R)-tert-butyldimethylsilyloxy-3,4,5,6-tetrahydro-2H-pyran-2- one.

In a second class of this embodiment are the compounds prepared wherein R_s is triphenylmethylthio-C_{1 3}alkyl. In a subclass are the compounds prepared wherein R, is methyl, R₁₁ is hydrogen and a, b, c, d are all single bonds or one of b, c. d is a double bond or b and d are double bonds. Illustrative of this subclass is the following compound:

a) 6(R)-[2-[8(S)-(2,2-Dimethyl-4-triphenylmethylthiobutyrlyloxy) 2(S),6(R)-dimethyl-1,2,6,7,8,8a(R)-hexahydronaphthyl-1 (S)ethyl]-4(R)-tert-butyldimethylsilyloxy-3,4,5,6-tetrahydro-2H-pyran-2-one.

In a third class of this embodiment are the compounds prepared wherein R_s is C, ₃alkanoyloxy-C_{1 3}alkyl. In a subclass are the compounds prepared wherein R, is methyl, R₁₁ is hydrogen and a. b, c, d are all single bonds or one of b, c or d is a double bond or b and d are double bonds. Illustrative of this subclass is the following compound:

a) 6(R)-[2-[8(S)-(4-Carbomethoxy-2,2-dimethylbutyrlyloxy)-2(S),6(R)-dimethyl-1,2,6,7,8,8a(R)-hexahydronaphthyl-1 (S)ethyl]4(R)-tert-butyldimethylsilyloxy-3,4,5,6-tetrahydro-2H-pyran-2-one.

A fourth class of this embodiment are the compounds prepared wherein Rs is C, ₃alkyloxyacyl(CH₂)_m where m is 0 to 3. In a subclass are the compounds prepared wherein R, is methyl, R_{1 1} is hydrogen and a, b, c, d are all single bonds or one of b, c or d is a double bond or b and d are double bonds. Illustrative of this subclass are the following compounds:

a) 6(R)-[2-[8(S)-(4-Acetyloxy-2,2-dimethylbutyryloxy) 2(S),6(R)-dimethyl-1,2,6.7,8,8a(R). hexahydronaphthyl-1 (S)ethyl]-4(R)-tert-butyldimethylsilyloxy-3,4,5,6-tetrahydro-2H-pyran-2-one.
b) 6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)-6(R)-tert-butyldimethylsilylmethyl-2(S)-methyl-1,2,4a(R)-5,6,7,8,8a(R)-octahydro-naphthyl-1 (S)ethyl]-4(R)-tert-butyldimethylsilyloxy-3,4,5,6-tetrahydro-2H-pyran-2-one.

A fifth class of this embodiment are the compounds prepared wherein R_s is
In a subclass are the compounds prepared wherein R₁ is methyl, R₁₁ is hydrogen and a, b, c, d are all single bonds or one of b, c or d is a double bond or b and d are double bonds. Illustrative of this subclass is the following compound:

a) 6(R)-[2-[8(S)-(2,2-Dimethyl-4-(N-methylacetamido)-butyrlyloxy)-2(S),6(R)-dimethyl-1,2,6,7,8,8a(R)-hexahydronaphthyl-1 (S)ethyl]-4(R)-tert-butyldimethylsilyloxy-3,4,5,6-tetrahydro-2H-pyran-2-one.

A sixth class of this embodiment are the compounds prepared wherein Rs is C, ₃ alkylthio-(CH₂)_m, phenylthio-(CH₂)_m, or C_{1 3} alkylsulfinyl-(CH₂)_m or phenylsulfinyl-(CH₂)_m. In a subclass are the compounds prepared wherein R, is methyl, R₁ is hydrogen and a, b, c, d are all single bonds or one of b, c or d is a double bond or b and d are double bonds. Illustrative of this subclass is the following compound:

a) 6(R)-[2(-8(S)-(2,2-Dimethyl-4-thiomethylbutyryloxy)-2(S),6(R)-dimethyl-1,2,6,7,8,8a(R)-hexahydronaphthyl-1 (S)ethyl]-4(R)-tert-butyldimethylsilyloxy-3,4,5,6,-tetrahydro-2H-pyran-2-one.

In a seventh class of this embodiment are the compounds prepared wherein R_s is phenyl or phenyl substituted with X and Y. In a subclass are the compounds prepared wherein R, is methyl, R₁ is hydrogen, and a, b, c, d are all single bonds or one of b, c or d is a double bond or b and d are double bonds. Illustrative of this subclass is the following compound:

a) 6(R)-[2-[8(S)-(2,2-Dimethyl-4-phenylbutyryloxy)-2(S),6(R)-dimethyl-1,2,6,7,8,8a(R)-hexahydronaphthyl-1 (S)ethyl]-4(R)-tert-butyldimethylsilyloxy-3,4,5,6-tetrahydro-2H-pyran-2-one.

An eighth class of this embodiment are the compounds prepared wherein R_s is C_{1 3}alkyl. In a subclass are the compounds prepared wherein R, is methyl, R₁₁ is hydrogen, and a, b, c, dare all single bonds or one of b, c or d is a double bond or b and d are double bonds. Illustrative of this subclass is the following compound:

a) 6(R)-[2-[8(S)-(2,2-Dimethylhexanoyloxy)-2(S), 6(R)-dimethyl-1,2,6,7,8,8a(R)-hexahydronaphthyl-1-(S)ethyl]-4(R)-tert-butyldimethylsilyloxy-3,4,5,6-tetrahydro-2H-pyran-2-one.

Another embodiment of this invention is the compounds of formula (I) prepared by the process disclosed herein where OR is the alkoxy residue of alcohol type (ii).
In one class of this embodiment are the compounds prepared wherein alcohol type (ii) E is CH₂CH₂ or CH = CH and R_{1 5}R_{1 6} R₁₇ R₁ and R₁ independently are hydrogen, fluoro, C, ₄ alkyl or hydroxy-C, ₄alkyl. In a subclass the compounds prepared by the process of this invention are those of formula (I) wherein alcohol type (ii) E is CH = CH. Illustrative of this subclass is the following compound:

a) (4R,6S)-E-6-[2-(3,5-Dimethyl-4'-fluoro-3'-hydroxymethyl[1,1'-biphenyl]-2-yl)ethenyl]-3,4,5,6-tetrah ydro-4-hydroxy-2H-pyran-2-one.

In a second subclass are those compounds of formula (1) wherein alcohol type (ii) E is CH₂CH₂. Illustrative of this subclass is the following compound:

a) (4R,6S)-6-{2-(3,5-Dimethyl-4'-fluoro-3'-hydroxymethyl[1,1'-biphenyl]-2-yl)ethyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one.

In the instant invention the acyl chloride, alcohol, alkali metal bromide and dialkylaminopyridine catalyst may be combined in any sequence. Preferably the acyl chloride is combined with an anhydrous alkali metal bromide in an appropriate solvent under an inert atmosphere for approximately 10-15 minutes before combination with the alcohol. Illustrative of appropriate solvents are: pyridine, 1.2 dichloroethane. methylene chloride, triethylamine and mixtures of pyridine with tetrahydrofuran. diethyl ether and methylene chloride.
The preferred solvent is pyridine. The preferred alkali metal bromide is lithium bromide.
The mole ratio of alkali metal bromide to acyl chloride can vary between 1.0-10.0 mole equivalents alkali metal bromide to 1.0 mole equivalent acyl chloride. The preferred ratio is 2.0 mole equivalents metal bromide to 1 equivalent acyl chloride. It is critical that the alkali metal bromide be dried prior to use and that it not thereafter be exposed to the atmosphere.
The mole ratio of acyl chloride to alcohol can vary between 2.0 to 3.0 mole equivalents of acyl chloride to 1.0 mole equivalents of alcohol. The preferred ratio is 2 equivalents acyl chloride to 1 equivalent alcohol. The acyl chloride is treated with an alcohol and an appropriate catalyst.
The catalysts employed are N, N, dialkylaminopyridines and cycloalkylated aminopyridines including 4,-N,N-dimethylaminopyridine, 4-pyrollidinopyridine, 4-(2,5-dimethyl)-pyrollidinopyridine and N,N,N',N'- tetramethyl-N"-4-pyridinyl-guanidine. The preferred catalyst is 4-N,N-dimethylaminopyridine. The amount of catalyst employed is approximately 0.1 mole equivalent to 1.0 mole equivalent acyl chloride.
The mixture of reactants, solvent and catalyst is heated between 25-75°C, preferably 70-75°C for 6-8 hours.

General reaction sequence:

In using the process wherein the reactant alcohol is of type (i) the precusor starting materials are compactin, mevinolin and their dihydro and tetrahydro analogs which are readily available or may be prepared according to fermentation procedures disclosed in U.S. Patent 3,983,140, U.S. Patent 4,049,495, U.S. Patent 4,231,938, U.S. Patent 4,294,846 and U.S.Patent 4,343,814, and the hydrogenation procedures disclosed in U.S. Patent 4,351,844. Reactants which contain a hydroxymethyl or a protected hydroxymethyl group in the 6-position of the polyhydronaphthyl ring are prepared according to the procedures disclosed in copending U.S. application S.N. 001933 filed January 9. 1987. The appropriate starting material of formula (7) is then hydrolyzed under the conditions disclosed in U.S. Patent 4,444,784 to afford the compounds of formula (8). The 4-hydroxy function in the lactone moiety of the compounds of formula (8) is protected with a suitable protecting agent, exemplified here as a dimethyl-t-butylsilyl group according to the procedure disclosed in U.S. Patent 4,444,784. Acylation of the 8'-hydroxy group is then accomplished using the appropriate acyl chloride, an alkali metal bromide and a dialkylaminopyridine catalyst. Silyl protecting groups are removed by treatment with tetra-butyl-ammonium fluoride following the procedure detailed in U.S. Patent 4.444,784. Triphenylmethyl protecting groups are removed by treatment with dilute acid.
The appropriately substituted acyl chlorides of formula (10) are commercially available or prepared from known starting materials utilizing standard chemical transformations. Specific examples of such transformations can be found in the following references:
Reactant alcohols of type (ii) are prepared from starting materials utilizing standard chemical transformations specific examples of such procedures are found in copending patent applications Serial No. 902.894 filed September 2, 1986 and 824,900 filed January 31, 1986.
The following examples illustrate the present invention and as such are not to be considered as limiting the invention set forth in the claims appended hereto.

EXAMPLE 1

Preparation of 6(R)-[2-[8(S)-(4-Acetyloxy-2,2-dimethylbutyryloxy)-2(S),6(R)-dimethyl-1,2,6,7,8.8a(R)-hexahydronaphtyl-1 (S)]ethyl]-4(R)-tert-butyldimethylsilyloxy-3,4,5,6-tetrahydro-2H-pyran-2-one

A dry 50 L 3-necked, round bottom flask, fitted with an overhead stirrer, thermocouple, and condenser was charged with 2,2-dimethyl-4-acetoxy-butyryl chloride (1.639 kg, 8.51 moles) and 6.8 L of dry pyridine and agitated under a N₂ atmosphere. Anhydrous lithium bromide (1.46 kg, 16.98 moles) was added portionwise over a period of 15 minutes via a plastic- bag secured to the neck of the flask. Commercial anhydrous lithium bromide (Aldrich, 99+%) was dried in vacuo at 135° C for 3 days prior to use.
The internal temperature rose to 55-60°C during the addition of LiBr to the_ pyridine/acid chloride mixture and the color changed from yellowish red to reddish brown.
The mixture was allowed to stir for 10-15 minutes at ambient temperature. A solution of 6R-[2-8(S)-hydroxy-2(S), 6(R)-dimethyl-1,2,6,7,8,8a(R)-hexahydronaphthyl-1(S)-ethyl]-4(R)-tert-butyldimethylsilyloxy-3,4,5,6-tetrahydro-2H-pyran-2-one (1.856 kg, 4.76 moles) in 5.4 L of dry pyridine was added in one portion. 4-N.N-Dimethylaminopyridine (104 g, 0.85 mole) was added and the mixture heated at 75°C under N₂. The reaction mixture turned dark brown as it was heated. The progress of the reaction was monitored by hplc. The reaction was typically carried to 98-99% conversion (usually 6-8 hours at 75°C). Product area % was usually 91-94%. At this point the level of unsaturated lactone by-product was approximately 1.5-1.8%. Prolonged heating increased the level of this impurity.
The reaction mixture was cooled to room temperature and some of the pyridine (6 L) removed in vacuo.
The thick, brown mixture was diluted with 4 L of ethyl acetate and 2 kg of ice and cooled to 15°C as the pH was adjusted to 2.7, with 6N HCI (7700 mL).
The acid was added at such a rate to keep the temperature <20°C. The pH was monitored with a pH meter.
More ethyl acetate (8 L) was added with vigorous agitation and the phases separated. The aqueous phase was further extracted with 12 L and 8 L portions of ethyl acetate. The combined organic phases were washed with 6 L of 1.2N HCI solution, 2 ^X 8 L of saturated NaHC0₃ solution and 8 L of saturated brine, dried over Na₂SO₄ (under N₂), filtered and evaporated in vacuo to a viscous, dark brown oil, which is used directly in the next step. The title compound was purified by column chromatography on silica gel using 25% ethyl acetate in hexanes to elute. The pure product was isolated as a colorless oil ¹H NMR (250 MHz, CDCl₃) 5.90 (d, 1 H, J = 10.0 Hz), 5.77 (dd, 1 H, J=10.0, 6.3 Hz), 5.50 (t, 1H, J = 3.75 Hz), 5.28-5.44 (m, 1 H), 4.44-4.71 (m, 1 H), 4.22-4.36 (m, 1 H), 3.93-4.19 (m, 2H), 0.40-2.75 (m, 24H; containing 3H singlet at 2.01, 3H singlet at 1.19, 3H singlet at 1.18, 3H doublet (J=7.5 Hz) at 1.07, 12H singlet at 0.87 (tert-butyl and methyl), 0.70 (s, 3H), 0.65 (s, 3H). IR(neat) 3020, 2960, 2940, 1738, 1475, 1370, 1240 cm ^-1.

EXAMPLE 2

Preparation of 6(R)-[2[8(S)-(2,2-dimethylbutryloxy)-2(S),6(R)-dimethyl-1,2,6,7,8,8a(R)-hexahydronaphthyl-1-(S)]ethyl]-4(R)-tert-butyldimethylsilyloxy-3,4,5,6-tetrahydro-2H-pyran-2-one.

Lithium bromide (2.95 g, 34 mmol, anhydrous) was added as rapidly as possible to a solution of 2,2-dimethylbutyryl chloride (2.28 g, 17 mmol) in anhydrous pyridine (13 mL) under N₂. When the temperature returned to 25°C, a solution of the alcohol (3.71 g, 8.51 mmol) and 4,4-dimethylaminopyridine (0.208 g, 1.7 mmol) in pyridine (10 mL) was added. The mixture was stirred at 70°C for 3.5 hours. The mixture was cooled to room temperature, poured into H₂0 (100 mL) and extracted with 2 ^x100 mL of ethyl acetate. The combined organic extracts were washed with 2 x 50 mL of 1.2N HCI, 50 mL of saturated NaHC0₃ solution, 50 mL of saturated brine, dried over anhydrous Na₂SO₄, filtered and evaporated in vacuo to give the title compound as a colorless oil.¹H NMR (300 MHz, CDCl₃) 5.97 (d, 1H, J=₉.₇₅ Hz), 5.75 (dd, 1H, J=₉.₇₅, 6.15 Hz), 5.43-5.52 (m, 1H), 5.26-5.35 (m, 1H), 4.48-4.64 (m, 1H), 4.22-4.33 (m, 1H), 2.17-2.65 (m, 5H), 0.70-2.05 (m, 35H; containing two 3H singlets at 1.11 and 1.08 ppm and a 9H singlet at 0.85 ppm), 0.06 (s, 3H), 0.05 (s, 3H).

EXAMPLE 3-15

Following the procedure in Examples 1 and 2 the following compounds of Formula (I) are prepared:

Claims

1. A process for the preparation of compounds of structural formula (I),

wherein:

n is 0 to 5

R₁ and R₂ are independently H or C_{1 10} alkyl or R₁ and R₂ together with the carbon atom to which they are attached form a carbocyclic ring of 3 to 8 carbon atoms;

R₃ and R₄ are independently H or C, ₃ alkyl, C_{3 7}cycloalkyl, C_{1 3} alkylthio, phenyl, phenylthio or substituted phenyl in which the substituents are X and Y and when n is 2 to 5, each of the R₃s and R₄S are independently hydrogen, C_{1 3} alkyl, C_{3 7}cycloalkyl or only one of the R₃s and R₄ S is phenyl or substituted phenyl;

Rs is hydrogen, halogen, C_{1 10} alkyl, phenyl or substituted phenyl in which the substituents are X and Y, or a group selected from:

a) trialkylsilyloxy-C_{1 10}alkyl or alkyldiarylsilyloxy-C_{1 10}alkyl;

b) triphenylmethylthio-C, ₁₀alkyl;

c) C, ₈alkanoyloxy-C_{1 4}alkyl;

d) R₇

-(CH₂)_m in which m is 0 to 3 and R₇ is C₁₅alkyl;

e)

-(CH₂)_m, in which R_s and Rg are independently C_{1 5} alkyl or R₈ and R₉ together with the nitrogen atom to which they are attached form a heterocycle selected from piperidinyl, morpholinyl, pyrrolidinyl, piperazinyl or thiomorpholinyl;

f) R₁ o

(CH₂)_m in which q is 0 to 2 and R_{1 0} is C_{1 5} alkyl or phenyl; X and Y independently are hydrogen, halogen, trifluoromethyl, C_{1 3}alkyl, C, ₃alkyl-oxy, C_{1 3}alkyl-thio, di(C, ₃ alkyl)N-

and

and OR is

wherein

R₁ is hydrogen or trialkylsilyloxy or alkyldiarylsilyloxy;

R_{1 3}is hydrogen or trialkylsilyloxy or alkyldiarylsilyloxy; a,b,c, d represent single bonds, one of a, b, c, or d represents a double bond or both a and c or both b and d represent double bonds, provided that when a is a double bond, A is

or

wherein

E is CH₂-CH₂ or CH=CH;

R₁ s R_{1 6} R₁₇ R₁ and R_{1 9} independently are

hydrogen,

halogen,

C_{1 4}alkyl,

C_{1 4} haloalkyl,

oxy-C_{1 4}alkyl,

C₁ s alkanoyloxy-C, ₄ alkyl,

C_{8 12} aralkanoyloxy-C, ₄ alkyl, or

C₇ or C₁ aroyloxy-C_{1 4} alkyl,

with the proviso that one or R_{1 5}R_{1 6} R₁ R₁₈ and R_{1 9} is oxy-C, ₄ alkyl or oxy-wherein oxy-the oxygen is directly bonded to the aromatic ring;

which comprises combining,

an alkali metal bromide, dialkylaminopyridine and a compound of structure (i),

or a compound of structure (ii),

wherein

R'is R'1 6 R'₁₇ R'₁₈ R'₁₉ are defined as R₁₅ R₁₆ R₁₇ R₁₈ R_{1 9} respectively provided that when R_{1 5} R₁₆ R₁₇ R₁₈ or R₁₉ is oxy-C_{1 4}alkyl or oxy-then R'₁₅ R'₁₆ R'17 R'₁₈ or R'₁₉ is hydroxy-C, ₄-alkyl or hydroxy respectively;

in a solvent, to yield compound (I).

2. A process of Claim 1 wherein OR is (a); and wherein Rs is selected from a group consisting of:

trialkylsilyloxy-C₁ 3 alkyl,

triphenylmethylthio-C_{1 3} alkyl,

C_{1 3}alkanoyloxy-C_{1 3} alkyl,

in which m is 0 to 3 and R₇ is C_{1 3}alkyl,

in which R₈, R₉ independently are C_{1 3} alkyl,

in which q is 0 to 2 and R_{1 0}is C_{1 3}alkyl, phenyl, or phenyl substituted with X and Y,

Phenyl or phenyl substituted with X and Y, or

C, ₃ alkyl; and wherein R₁ is methyl, R₁₁ is hydrogen and a, b, c, d, are all single bonds or one of a, b, c, d, is a double bond or b and d are double bonds; and wherein R₂ is methyl, R₃ and R₄ are hydrogen; and wherein R₁₃ is hydrogen.

3. A process of Claim 2 wherein R_s is C, ₃alkanoyloxy-C_{1 3} alkyl.

4. A process of Claim 3 wherein the compound prepared is 6(R)-[8(S)-(4-Acetyloxy-2,2-dimethyl- butyryloxy)-2(S), 6(R)-dimethyl-1,2,6,7,8,8a(R)-hexahydronaphthyl-1(S)]ethyl]-4(R)-tert-butyldimethylsilyloxy-3,4,5,6-tetrahydro-2H-pyran-2-one.

5. A process of Claim 1 wherein OR is (b); and wherein E is CH =CH; R₁₅ R₁₆ R₁₇ R₁₈ R₁₉ independently are methyl, oxy-methyl, fluoro, and hydrogen.

6. A process according to any one of the preceding claims wherein the alkali metal bromide is lithium bromide;

7. A process according to any one of the preceding claims wherein the dialkylaminopyridine catalyst is selected from a group consisting of di(Ci _salkyl)aminopyridine, 4-pyrrolidinopyridine, 4(2,5-dimethylpyr- rolidinopyridine and N,N,N',N'-tetramethyl-N"-4-pyridinyl-guanidine.

8. A process according to Claim 7 wherein the dialkylamino pyridine catalyst is 4,4-dimethylaminopyridine.

9. A process of Claim 2 further comprising the treatment of compound (I) with tetrabutylammonium fluoride and dilute acid to form:

wherein

R₆ is defined as Rs provided that trialkylsilyloxy-C_{1 10} alkyl or alkyldiarylsilyloxy-C, ₁₀alkyl is hydroxy-C_{1 10} alkyl, and triphenylmethylthio-C, ₁₀alkyl is thio-C, ₁₀alkyl;

and OR' is

wherein

R'_{1 3}is hydrogen or hydroxy; provided that when a is a double bond. A' is

10. A process of Claim 5 further comprising the treatment of compound (I) with tetrabutyl-ammonium fluoride and dilute acid to form,

wherein

R'₆ is defined as R_s provided that trialkylsilyloxy-C, ₁₀ alkyl or alkyldiarylsilyloxy -C_{1 10}-alkyl is hydroxy-C_{1 10} alkyl and triphenylmethylthio-C, ₁₀ alkyl is thio-C_{1 10} alkyl, and

OR" is